Recent developments, including contributions from the applicant laboratory, have opened new opportunities for investigation of dynamic processes on mus-ms time scales using nuclear magnetic spin relaxation measurements. Motions on these time scales reflect large amplitude loop motions, relative motions between domains, collective "breathing" of protein cores, ligand-binding or oligomerization reactions, and overall biological functions such as molecular recognition, substrate binding or product release by enzymes, and mutations that affect dynamical properties on these time scales can be associated with significant pathology including misfolding. The existence of large amplitude intra- molecular conformational changes in proteins have been inferred from comparison of structures of a given protein in different crystal forms, a given protein in free and ligand-bound states, or a series of homologous proteins, as determined by x-ray crystallography or NMR spectroscopy. Ligand-binding, oligomerization or folding kinetics have been investigated by many biophysical techniques, including NMR and optical spectroscopic techniques, and perturbative approaches, such as rapid mixing, and temperature jumps. However, only solution NMR spectroscopy can confirm the occurrence and determine the kinetic rates in the solution state of dynamic processes at equilibrium and with atomic site resolution in the absence of potential influences from intermolecular interactions in the solid state,, and without potential complications introduced by non-native modifications necessary for other solution state spectroscopic techniques. The proposed research has four primary objectives: (1) the development of improved experimental and theoretical methods for characterizing protein dynamics on mus-ms time scales; (2) evaluation of hypothesized mechanisms coupling mu-ms conformational dynamics in triose phosphate isomerase and other proteins; (4) measurement of local variations in folding rates in the B1 domain of protein G and other proteins. Successful completion of these goals will enable the application of the techniques developed to a wide range of additional protein systems of biological interest.